Multiple myeloma (MM) is a cancer of the plasma cell, which primarily develops in the elderly population. The progression of the tumor is well understood, and it can be diagnosed by the presence of multiple myeloma cells in the bone marrow and monitored by the amount of antibody secretion from the clonal population of plasma cells. A premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS) develops at certain rates in the U.S. population: 3% at age 50, 5% at age 70, and 7% by age 85; approximately 1% of MGUS patients progress to multiple myeloma on an annual basis (Kyle et al., 2006). The molecular causes for progression from MGUS to MM are unknown. After the onset of the cancer, multiple myeloma patients suffer from several symptoms, including calcium dysregulation, renal failure, anemia, and bone lesions. A diagnosis of multiple myeloma is established using blood and urine tests. For advanced stage patients, complete skeletal surveys are also used to examine the damage caused by multiple myeloma in the bone marrow. Staging with serum calcium, creatinine, hemoglobin, and most importantly, the concentration of the “monoclonal serum protein” was established in 1975 by Durie and Salmon (Durie and Salmon, 1975). The International Staging System determined in 2005 uses those markers as well as serum albumin and β-2-microglobulin (Greipp et al., 2005). The survival statistics indicate the importance of early detection and proper staging, and show the devastating impact of multiple myeloma. Stage I patients have median survival times of 62 months, stage II 45 months, and stage III patient median survival is reduced to 29 months.
Despite the highly specific and easily detectable biomarkers, many challenges still exist for MM treatment. Several different treatment regimens are under investigation: these strategies have been the subject of numerous recent reviews (Fonseca and Stewart, 2007; Chanan-Khan and Lee, 2007; Thomas and Alexanian, 2007; Falco et al., 2007). Novel therapeutic strategies include proteasome inhibition with agents like bortezomib (Voorhees and Orlowski, 2007; Manochakian et al., 2007) and a combination of cancer cell targeting and immune modulation with thalidomide derivatives like Lenalidomide (Singhal and Mehta, 2007). While each of these agents can have some success against multiple myeloma cells, proteasome inhibitors are the only molecularly guided therapy to date: treatment is more effective for patients with myelomas that secrete high levels of monoclonal antibodies (Meister et al., 2007). The use of the other agents is directed by the expected tolerance for side effects rather than molecular targeting. Regardless, these agents improve the patient outcome when compared to the current standard of care (Ma et al., 2003), and drug combination strategies are currently in clinical trials (Srikanth et al., 2008; Richardson et al., 2007; Merchionne et al., 2007). Proteomic research may contribute to guidance of existing and emerging therapies. Identification of novel targets including c-Jun and the Fanconi anemia pathway (Chen et al., 2005) also offers opportunities to examine protein expression, binding partners, and post-translational modification. Furthermore, the bone marrow microenvironment is critical for progression of multiple myeloma and likely contributes to drug resistance; (Li and Dalton, 2006; Harlehurst et al., 2003; Dalton, 2003) this knowledge has led to preclinical models examining multiple myeloma in the context of the bone marrow microenvironment. Plausible targets in the bone marrow microenvironment include cytokine signaling, e.g. IL-6, (Chauhan et al., 1997; Urashima et al., 1997) and integrin mediated drug resistance (Damiano et al., 1999). Proteome analysis may make a significant contribution here as well.
Patient monitoring strategies present significant challenges, particularly in the detection of MGUS patients most likely to develop multiple myeloma and ongoing assessment of relapse or recurrence in previously treated multiple myeloma patients. Many MM patients who have undergone treatment are repetitively checked at two week or four week intervals, leading to high numbers of clinic visits and collection of large volumes of blood. Methods for patient sampling and detection of the monoclonal serum protein are presented from a process chemistry standpoint. Process chemists use extensive background knowledge of synthesis, analysis, and engineering to redesign industrial assembly lines or improve individual steps in manufacturing.